KR820001992B1 - Process for preparing a flavan derivatives - Google Patents

Abstract

Title compds. I [ R = H or two substituents(selected from halo, NO2, cyano, CF3, C1-4 alkylamino, C1-4 alkyl), R1 = H or two substituents (selected from halo, NO2, cyano, CF3 alkylamino, alkoxy, OH), which exhibited virucidal activity, were prepd. by different methods. A mixt. of 2'-hydroxy-4-methylchalcone, H3PO4, and MeOCH2CH2OH was refluxed to yield 4'-methylflavanone and clemmensen redn. of the products gave 4'-methylflavan.

Description

Method for producing flavan derivative

The present invention relates to a method for producing flavan derivatives which are active against anti-viral agents, in particular non-viral.

Vivirus infections are infections caused by other viruses and allergic reactions, such as jangbairu and coronaviruses, which can also cause colds but have a factor for about 70% of colds. Human beings all over the world are susceptible to virus infections, which are a major factor in disease and cause incompetence, causing even greater economic problems.

Common cold spreads through scattered droplets when an infected person coughs or sneezes, which is then scattered by others and causes respiratory infections. After 48 hours-2 weeks of incubation, the infected person suffers from inferiority due to sore throat, coughing, sneezing, increased mucous secretions and secondary bacterial infections.

There is some resistance to the virus virus type after infection but no immunity to other serotypes. Continued reinfection with serotypes prevalent in particular communities maintains a certain level of resistance to these viruses in most individuals. The common cold is the result of having only two or three new serotypes per year.

Since there is no cross-immunity, there are at least 120 known immunogenic traits of the virus-type serotype and wax injection is not a viable treatment. Air hygiene has been attempted as a way to reduce the incidence of colds but has not been successful. The only practical treatment is likely to be by compounds which are suitable for administration to humans and which are preferably active against all common serotypes or at least a wide range of viviruses. Despite great research efforts, such compounds have not appeared to date and no chemotherapy agents have been selected for these diseases.

However, it has now been found that flavans and their derivatives are active against certain viruses, including, for example, picorna, menken, arbo, myxo, corona, herpes and adenoviruses, which cause respiratory infections. In particular these compounds are active against viviruses and in particular against serotypes 1B, 2 and 9. Apart from a few compounds in this class, newer derivatives have also been prepared and tested that are known but not reported to have adequate activity in this respect. It has been observed that these compounds can inhibit vivirus during in vitro testing of cultures and some also exhibit activity against other viruses such as herpes, influenza and measles virus. In addition, the same compound has activity against the virus in animal studies, particularly when administered at a suitable dose in humans and other mammals. At the same time the flavans themselves have absolutely good activity against viviruses and the substituted derivatives have similar or enhanced activity depending on the nature and position of the substituents.

The compound also showed very low toxicity with LD ₅₀ at an excess of 500 mg / kg. Activity can be detected by platelet arrest and can also be measured by platelet reduction. Positive assays include the formation of monolayer cell cultures in a petri dish, infected with virus suspension, and then coated with the culture as a gel nutrient agarose. The gel ensures no diffusion of the virus through the incubation and confirms that localized cell breakdown or platelets are formed.

In the platelet blocking test, a margin plate to which 0.01 ml is applied when the solution of the compound is impregnated is placed on top of the agarose gel. The compound is then diffused through the bone gel so that the largest concentration of the compound will be located around the filter board and the lowest concentration will be directed around the petri dish. The potency of the compounds can be detected by observing the lowland of platelet formation.

Detectable activity is measured by a platelet reduction assay. Known molar concentration ranges of compounds are related to nutrient agarose application. Platelet inhibition is proportional to the concentration of the compound. Platelet count is expressed as a percentage of arrest and a dose response curve is plotted. From this curve 50% of the effective amount (ED ₅₀ ) can be evaluated.

Some flavans are already known in the chemical literature. However, there are no public disclosures of 3, 3 ¹ , 4, 4 ¹ , 5, 7-hexahydroxy flavans, which can be used for the treatment of various diseases, and others which propose their use for the treatment of humans or animals other than Did not. In other words, 3-hydroxyflavan (Lancat: 2; 1153 (1977): various 3, 6-dialkyl or dialkoxyflavanes (USP) has been attempted without success with viral hepatitis, including the aforementioned flavans. 3555 047) It can lower blood cholesterol levels; 1-epi-3 ¹ , 4 ¹ , 5 ', 5', 7-pentahydroxyflavan 3-ol (UM Gazave), a potent anti-ascorbutin Fruits: 32: 257-284 (1977) and 3, 3 ¹ , 4 ¹ , 5, 7-pentahydroxy flavans (French Patent No. 988332 and No. 3), which may have a vitamin-positive effect on capillaries. 988333), etc. Thus, according to the present invention there is provided a flavan or derivative thereof having the following structural formula (1) or a specific pharmaceutically acceptable salt thereof.

R ¹ and R ² in the above structural formulae represent substituents selected from the classes described below for the purpose of preventing or treating virus infection. Meanwhile, the compound of formula (1) is provided as a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient.

In structural formula (1), R ¹ represents hydrogen or up to 4 substituents and R ² represents hydrogen or up to 5 substituents. R ¹ and R ² are not as preferred, and most preferably represents a substituent of up to 2, respectively, represents a substituent of one R ¹ and R ^2, respectively.

Preferably the compound has an R ¹ substituent on the 6 or 7 above, or 2, 3 ^1, 4 ^1, 5 ^1, or ² substituents at the ^1-R 6 gatneunde a particularly preferred will be the top 6 and above ^41. It has also been found that the size of this substituent is related. For example, the increased activity in the 4 ^1st and 6th positions is with the aid of substituents having a [R] _D value of 15 or less, preferably 10 or less.

This [R] _D value is S. Glasstone, Text-book of Physical Chemistry, 2nd Edn. Modified molar capacity as described in 1948, Macmillan, London, Pg 528. It can be calculated from the molar mass M, density ρ and refractive index η according to the following equation.

Values for many substituents were determined by Vogel and throughout 1948 the J. Chem. Was published. Advantageously, the substituents are halogen atoms or nitro, cyano, trifluoromethyl, lower alkyl, lower alkoxyl, amino or hydroxyl groups chloro, nitro, cyano and chlorine is the most preferred substituent if preferred.

Conditions of choice for the type, position and number of substituents can be conveniently combined to increase the increase in activity in all likelihood. However, the ultimate properties of the compounds in terms of use also depend on other physical and biological characteristics.

In another aspect, the present invention provides a compound of the general formula (II)

Or pharmaceutically acceptable salts thereof in the above structural formulas. Here to both the R ¹ and R a or R ¹ and R ² of ² as a prerequisite one thing locations or whichever of the following: a halogen atom, or a nitro, cyano, trifluoromethyl, lower alkyl, lower alkoxyl, One or more substituents selected from the group comprising amino loweralkylamino or hydroxyl groups.

a) the compound has only one of the above substituted weights other than 4 ^1- , 5-, or 7-methoxyl, 6-methyl, 6-amino or 7-hydroxyl groups or

b) The compound is a cyclic aromatic group other than 4 ¹ -methoxyl group or 4 ¹ -hydroxyl group with 7-methyl or 7-hydroxyl group together with 6- or 7-methoxyl or 7-hydroxyl group. Have only one of the substituents or

c) The compound is 5, 7-dimethyl or 5, 7-dihydroxyl, 5-methoxyl-7-hydroxyl, 6-butyl-7-hydroxyl or 3 ¹ , 4 ¹ -dimethoxyl or dihydroxy Having only two of both substituents located at one of the aromatic rings other than the actual groups or

d) The compound is a combined 5, 7- of any one of 4 ¹ -methoxyl or 3 ¹ , 4 ¹ -dihydroxyl or 3 ¹ , 4 ¹ -dimethoxyl, or 4 ¹ , 6-dihydroxyl. 5-hydroxyl-4-methoxyl or together with 4 ¹ , 7-dimethoxyl or other 7-hydroxyl or methoxy 7-silicone with one of dimethoxyl or other 3 ¹ -or 6-methoxyl It has three or four of the said substituents other than a 5, 6, 7, 8- tetrachloro substituent other than that.

Salts of compounds (I) or (II) may be formed when hydroxyl or amino substituents are present. Pharmaceutically acceptable salts are salts of mineral acids such as hydrochloric acid or sulfuric acid, salts of organic acids such as lactic acid, maleic acid and acetic acid and salts of bases such as sodium or potassium.

Compounds belonging to this class may have substituents depending on the selectivity as described above in relation to formula (I). The novel compounds with the highest activity in the experiment are 4 ¹ -fluoro-flavane, 3 ¹ , -4 ¹ -dichloro-6-methylflavane, 4 ¹ -methyl-7-methyl-flavane, 6-chloro-4 ^{1-methyl-half} Plastic and ^41, 6-dichloro Plastic semi-Plastic half, 6-methoxyl-Plastic half, ^41-methyl Plastic half, 6-chloro-4 ^1-methyl.

In another aspect, the present invention provides a method for preparing a compound of formula (I) or (II), including any of the following.

a) reduction of the compound of formula III by essentially known methods

In the above structural formula, R ¹ and R ² are as previously defined in formula (I) or (II), R ³ and R ⁶ are hydrogen atoms, R ⁴ and R ⁵ are the same or different, hydrogen or halogen atoms or It is a hydroxyl group on the premise. That is, only one of R ⁴ and R ⁵ is hydrogen or R ⁴ and R ⁵ together form a double bond or one of the double groups R ³ and R ⁴ or R ⁵ and R ⁶ are oxo-, Represents a ketal, thioketal or dithioketal group and one of the other groups is a hydrogen atom, the other is a hydrogen or halogen atom or a hydroxyl group or tautomer or salt thereof; Or cyclization of the compound of formula (IV) followed by continuous reduction or reduction followed by cyclization either by separation of intermediates or by essentially known methods.

R ¹ and R ² in the above structural formula are as defined in a) above; or

c) in the condensation of compounds of formula (V) by essentially known methods,

In the above structural formula, R ¹ is a hydroxyl group or a halogen atom as defined in the above a), and condensed as a compound of the following formula (VI).

R ² in the above structural formula is as defined in a) above; It is then optionally transposed to a compound of formula (I) or (II) followed by formation of another compound of formula (I) or (II) by essentially known methods. It is also possible by reacting compounds having amino or hydroxyl substituents in a liquid medium as suitable photoacids or organic acids or bases if desired to form salts of the compounds of formula (I) or (II).

There are a number of well-known techniques that can utilize catalytic hydrogenation using a catalyst such as palladium charcoal, chromium oxide or raninickel or a) methods such as Clemmensen and Wolff Kischner reduction.

Klemmensen reduction examples include EL Martin, Organic Reactions, (1942) 1, 161) and variations of the technology (eg E. Vedej's, Organic Reactions (1974), 22, 412 BL Verma, et al, Indian J. Chem (1962) 3 (12), 565 MM Bokadia & BL Verma, Chem. And Ind. (1964), 235, are particularly convenient for reducing ketone derivatives of formula (III). Wolff Kischner reduction can be applied only to compounds of formula III, wherein R ³ and R ⁴ together represent an oxo group. The reaction involves the formation of a hydrazone derivative of the ketone, which intermediate is then reduced.

Reduction of dithioketal can be accomplished, for example, with the use of raninickels in dioxane. (E. J. keogh, et al, Chem. And Ind. (1961) 2100).

Flavanones can also be reduced using lithium aluminum hydride mixed with aluminum chloride (MM Bokadia at al J. Chem. Soc. (1962) 1658; BL Verma et al Indian J. Chem. (1965) 3 (12) 565).

Flav-3-ene derivatives of formula III are conveniently reduced using sodium hydroxide or other complex hydride reagents. (J. W. Clark-Lewis and R. W. Jemison, Austral. J. Chem. (1968) 21, 2247).

Catalytic reduction of the compounds of formula III is particularly useful for the halogenated derivatives of JW Clark-Lewis (above), M. Suzuki et al, Nippon Kagaku Zasshi (1968) 89 (9), 878-82 and (1969) 90 ( 4) 397-400 and R. Mozingo and H. Adkins, J. Am. Chem. Soc., (1938) 60, 669 may be effected by significant techniques.

In the method of b), the compound of formula IV can be cyclized by treating as hydrochloric acid while producing a flavilium salt and reduced to flavan by catalytic hydrogenation. (Eg USP 3,555,047).

The chalcones can be reduced to the dihydrochalcones by catalytic hydrogenation. Desired flavans can be obtained by treating dihydrochalcone with zinc chloride in benzene (eg Van Allen, Reynolds and Regan, J. Org. Chem. (1967) 32, 1897).

In addition, chalcone can be provided with the corresponding (2-hydroxyphenyl) ethylphenylcarbinol by treatment with a complex hydride reducing agent such as sodium borohydride or cyanoborohydride. The latter can then be cyclized using an acid catalyst such as acetic acid or P-toluenesulfonic acid.

The combined reduction and cyclization of the chalcone of formula IV results in the effect of treating this compound as a mixture of lithium aluminum hydride and aluminum chloride (MM Bokadia et al, J. Chem. Soc. (1962), 1658).

c) Condensation can be effected by exothermic reaction in the method of paragraph. In the case of a compound of which X is a halogen atom, it is effective by using a Friedel Craft type catalyst in a suitable solvent. In this case, tin chloride is the preferred catalyst and 1,2 dichloroethane is the preferred solvent. The target product can be obtained in the case of low boiling flavan derivatives, in particular by distillation after exothermic condensation, or by chromatography when the chromatography is suitable. On the other hand, this condensation can occur in the presence of acids, in particular in the presence of sulfuric acid (e.g. RR Schmidt, Tet Letters. (1969), 60, 5279; K. Hultzsch, J. Park. Chem. (1941), 158, 275 M). Wakselman and M. Vilkas, CR hebd. Seances, Acad. Cci. (1964) 258, 1526).

In structural formula (III), R ³ and R ⁴ are halogen, and R ⁵ and R ⁶ are all synthesized by the clemmensen reduction of flavanone of structural formula (III), which together represent an oxo group, or a derivative thereof or alcohol. For example, palladium charcoal is used in a suitable solvent such as ethanol or lower carboxylic acid for example acetic acid or aromatic solvent such as toluene to form a double bond in which R ⁴ and R ⁵ together form a double bond (III). It has been found to be particularly convenient to synthesize flavans and their derivatives by the catalytic reduction of flav-3-ene).

Flav-3-ene can be preferably obtained by treating the 2'-hydroxy chalcone as a complex hydride, preferably sodium borohydride.

b) Reduction and cyclization according to the process of paragraph (b) are most preferred by treating the compound of formula (IV) as sodium borohydride in an ether solvent, preferably in tetrahydrofuran, followed by cyclization with a suitable acid, preferably acetic acid. Is carried out.

Condensation according to the method of c) is most preferably carried out by heating the compounds of formulas (V) and (VI) to a temperature of 150-250 ° C. The compound of formula III can be prepared by acid or base catalyzed cyclization of chalcone of formula III.

R ¹ and R ² in the above structural formula are the same as defined in item a). These chalcones and chalcones of the above formula (IV) are prepared by Knoevenagel condensation of suitably substituted acetphenones and benzaldehyde derivatives. (Nielsen, Organic Reactions. (1968), 16, the reaction can be generated by acid or base catalysis in aqueous or organic medium using base or organic or inorganic acids, such as alkali metal hydroxides or alkoxides).

The acetophenone and benzaldehyde derivatives required to prepare the above starting materials, intermediates and chalcones (IV) and (iii) are commercially available or can be prepared by essentially known methods. (See reference to example above).

Furthermore, the present invention provides pharmaceutically acceptable salts thereof, together with pharmaceutical compositions, tautomers or pharmaceutically acceptable carriers thereof, comprising the compounds of formula (I) or (II). In a particular aspect, the present pharmaceutical compositions comprise a compound of formula (I) or (II) in an effective single dosage form.

As used herein, the term "effective single dose" is indicated to mean a sufficient predetermined antivirus dose effective against virus in the animal. Pharmaceutically acceptable carriers are acceptable materials known for dosage purposes which may be solid, liquid or gas which are also inert, medically acceptable and compatible with the active ingredient.

Such pharmaceutical compositions may be administered parenterally, orally or intranasally, or as suppositories, as inhalants, as ointments, creams, sprays, powders, or vapors, or to treat a Vivirus infection When using it can be administered as a nasal drop.

For such infections the composition is administered orally or parenterally at the following dosage levels calculated as free flavans. Ie, about 0.125 μg-1.25 mg / kg body weight, preferably 0.25 μg-0.125 mg, most preferably 8-30 g per kg body weight of mammal, in amounts of 10 μg-100 mg several times a day, convenient Preferably every single dose of 0.1-10 mg.

For oral administration, the micropowders or granules may comprise diluents, dispersants and / or surfactants and may be handmade with water or syrups, as dry or non-aqueous solutions or suspensions containing capsules or perfumes in a dry state. It may contain a suspending agent; In tablets, it may contain a binder and a suspending agent; Or as a suspending agent or syrup in water. Perfumes, preservatives, suspending agents, thickening agents or emulsifiers may be contained as desired or as required. Tablets, capsules, granules and the like are preferred and these may be coated. On the other hand, the composition is administered as a solution of the compound of formula (II) or (II) in a medium based on a suitable oil.

The composition may also be administered using inhalants, aerosols, sprays, or the like, or by inhaling the vapor containing the compound of formula (I) or (II).

For parenteral administration or as aerosols, sprays or drops, the compound may be made into an aqueous solution at a concentration of about 0.1-10%, more preferably 0.1-1% and most preferably 0.2% W / V. have. The aqueous solution may contain an antioxidant, a buffer, and the like.

A more detailed aspect of the present invention provides a method for treating virus infection in a mammal, as defined above by the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described above. do.

Administration is preferably administered by oral, intranasal or parenteral methods.

The invention will be illustrated by reference to the following examples, which in no way limit the scope of the invention.

[Example 1-47]

Preparation of Calcon Intermediates

Substituted benzaldehydes used in the following examples can be obtained commercially. The 0-hydroxyacephenone used in the following examples is commercially available and its substituted derivatives have been prepared by the Fries intramolecular potential of the corresponding phenylacetate derivatives or by other methods.

Example 1

Preparation of 2'-hydroxy-5'-methylchalcone

To a solution of 2-hydroxy-5-methylacetophenone (30.0 g) and benzaldehyde (21.2 g) in ethanol (250 ml) was added a solution of potassium hydroxide (39.5 g) tablets dissolved in water (100 ml).

The clear solution was left at room temperature for 4 hours during which time the solution turned red. It was poured on ice and concentrated hydrochloric acid (80 ml) was added. The precipitated yellow was then filtered off chalcone, washed with water and recrystallized from ethanol to give 2'-hydroxy-5'-methylchalcone (31 g) as orange crystals (melting point 107-108 ° C).

Example 2-44

The compound of Example 2-44 was prepared by the same method as employed in Example 1, using appropriate substituted starting materials.

Example 44

5-bromo-2-hydroxy-4'-methoxychalcone

5-Bromosalicylaldehyde (20.1 g) and P-methoxyacetophenone (15.0 g) were dissolved in ethanol (80 ml) and a solution of potassium hydroxide (26.5 g) dissolved in water (40 ml) was added while cooling. The reaction mixture was left overnight and the excess hydrochloric acid was acidified.

Precipitated 5-bromo-2-hydroxy-4'-methoxychalcone was filtered off, washed with water and recrystallized from ethanol. 27.5 g. Melting point: 177-179 ° C.

Example 45-47

The compounds of Examples 45-47 were prepared in a manner very similar to those employed in the Examples using appropriate substituted fixatives.

Example 48-98

Preparation of Flavan from Calcon of Examples 1-47.

Example 48

Preparation of 4'-methylflavan

The 2'-hydroxy-4-methylchalcone (7.3 g) of Example 13 was boiled under reflux for 8 hours with 85% phosphoric acid solution (22 ml) in 2-methoxyethanol (219 ml). The reaction mixture was diluted with water (1 liter) and the oily precipitate was extracted with dichloromethane (300 ml). The organic extract was separated and washed with water and saturated sodium bicarbonate solution. Filtration and evaporation yielded a residue of 4'-methylflavanone that was turbid with the starting chalcone.

The intermediate flavanone could not be separated into pure form. Because the chalcone-flavanone potential is in equilibrium, it allows flavanones to be easily separated from chalcones, which are less or less complete, or generally less soluble. Thus, Klemmensen reduction was carried out on the crude chalcone-flavanone mixture and on alumina chromatography to remove the phenolic impurities thus formed.

Crude flavanone was dissolved as a mixture of acetic acid (200 ml) and concentrated hydrochloric acid (45 ml), warmed to 50 ° C. and added to wet zinc amalgam (prepared from 60 g of zinc mal and 6 g of mercury acetate). The mixture was shaken for 15 minutes and heated in a steam bath for 15 minutes after being left for 30 minutes. Residual zinc was filtered off and the filtrate was diluted with water. The crude product was extracted with toluene and the extract was washed with water and saturated sodium bicarbonate solution. The residue was obtained by evaporation, which was poured onto chromatograph on alkaline alumina and eluted with toluene. The first fraction obtained by evaporation of the solvent was recrystallized from ethanol to obtain a melting point of 94 ° C. of 4'-methylflavan (1.4 g).

Example 49-64

The compounds of Examples 49-64 were prepared in exactly the same manner as employed in Example 48 using the appropriate chalcones of Examples 1-47.

* 0.05mmHg = 6.7Pa

** 0.15mmg = 20Pa

Example 65

Preparation of 4'-Chloroflavan

4-chloro-2'-hydroxychalcone (5.17 g) was boiled under reflux for 5 hours as a mixture of ethanol (250 ml) and sodium acetate (4.10 g of anhydride) in solution or water (25 ml). The reaction mixture was diluted with water and left overnight. A precipitate of solids was filtered off, washed with water and dried. When recrystallized from petroleum ether (boiling point 80-100 degreeC), 4'- chloroflavanone (1.50g) and melting | fusing point 96-98 degreeC were obtained.

4'-Chloroflavanone (4.0 g) was dissolved in acetic acid (150 ml) and concentrated hydrochloric acid (20 ml) and added to wet zinc amalgam (prepared from 80 g zinc and mercury chloride (6.4 g)). The reaction mixture was stirred for 1 hour and then left overnight. The xantrum zinc was filtered off, washed with water, the filtrate and tax solution combined and diluted with water. The oily product was extracted with ether and the extract was washed with water and saturated sodium bicarbonate solution. It was dried over magnesium sulfate, filtered and evaporated and the residue was poured onto chromatograph eluting with toluene on alkaline alumina. The eluate was evaporated and the residue was recrystallized from ethanol to give 4'-chloroflavan, melting point 76-77 ° C.

Example 66-76

The compounds of Examples 66-76 were prepared in an analogous manner to the techniques employed in Example 65 using the appropriate chalcones of Examples 1-47.

* 0.lmmHg = 13.3Pa

** 0.07mmHg = 9.3Pa

Example 77-80

The compounds of Examples 77-80 were prepared in exactly the same manner as employed in Example 65 using the appropriate chalcones of Examples 1-47 except that the intermediate flavanone was not purified.

* 0.06mmHg = 8Pa

Examples 81 and 82

The compounds of Examples 81 and 82 were carried out by chromatography on silica gel eluting as a special solvent on silica gel since the purification was incompatible with alumina.

* 0.45mmHg = 60Pa

Example 83

Preparation of 6-chloroflavan

5'-Chloro-2'-hydroxychalcone (25.0 g) was dissolved in ethanol (125 ml) and an aqueous solution of 1.5% sodium hydroxide (375 ml) was added. The mixture was stirred at room temperature for 4 hours, the solid was filtered, washed with water and dried to give 6-clotroflavanone (16.65 g) and a melting point of 90-03 deg. The construction product recrystallized from 60-80 degreeC petroleum ether had melting | fusing point 95-96 degreeC. The present flavanone (4.0 g) was dissolved in acetic acid (160 ml) and concentrated hydrochloric acid (20 ml) and added to amalgamated zinc (from 40 g of zinc powder in powder) and mercuric chloride (0.5 g). The mixture was stirred for 1 hour and left overnight. Residual zinc was filtered off and the filtrate was diluted with water. The oily precipitate was extracted with ether and the extract was washed with water and saturated sodium bicarbonate solution, dried over magnesium equivalent, filtered and evaporated. The residue was chromatographed on alkaline alumina eluting with 60-80 ° C. petroleum ether to give Budney 6-chloroflavan (0.52 g) melting point 71-72 ° C.

Example 84-85

The compounds of Examples 84 and 85 were prepared in exactly the same manner as employed in Example 83 except that the flavanone intermediate in Example 85 was not characterized.

* 0.5mmHg = 67 Pa

** 0.1mmHg = 13 Pa

Example 86

Preparation of 4 '-(N, N-dimethylamino) flavane

4 (N, N-dimethylamino) -2′-hydroxychalcone (6.6 g) was boiled with 2N-hydrochloric acid (100 ml) for 3 hours under reflux. A solution of 4 '-(N, N-dimethylamino) flavanonehydrochloride thus formed was added to a suspension of amalgamated zinc (from zinc only (40 g) and mercury chloride (0.8 g)) in 30 ml of water. The mixture was stirred at 45 ° C. for 45 minutes. The residual zinc was separated from the aqueous solution by decantation and stirred with acetic acid (15 ml) and then filtered. The zinc was further washed with acetic acid, the tax solution and the filtrate were combined, diluted with water, and extracted with toluene. The extract was washed with water, dried over magnesium equivalent and filtered and evaporated. The residue was poured onto crobatograph on neutral alumina and the first fraction was evaporated to give crystalline 4 '-(N, N-dimethylamino) flavane. This was recrystallized from methanol and then recrystallized again with 60-80 ° C. petroleum ether to obtain a target product of 0.7 g and melting point of 77-78 ° C.

Example 87

Preparation of 4'-aminoflavane

4-acetylimino-2'-hydroxychalcone (7.20 g) was boiled with acetic acid (100 ml) and concentrated hydrochloric acid (2 ml) under reflux for 7 hours. A clear solution of 4'-aminoflavanone hydrochloride was treated with amalgamated zinc (from zinc powder (40 g) and mercury chloride (0.8 g)) under nitrogen gas and then stirred at room temperature for 4 hours. Residual zinc was filtered off and washed with acetic acid. The combined filtrate and filtrate were neutralized with bicarbonate solution and the oily product was extracted with dichloromethane. The solution was poured onto chromatograph on neutral alumina eluting with dichloromethane. The first fraction was evaporated to give a solid 4'-aminoflavan. This crystallized from 60-80 degreeC petroleum ether boiling, and it cooled to -10 degreeC, and obtained the target object of 180 mg and melting | fusing point 85-87 degreeC.

Example 88

Preparation of Flavan

2'-hydroxychalcone (9.0 g) was stirred with ethanol (100 ml) at room temperature and sodium borohydride (3.05 g) was added in small portions at the same time. After stirring for 2 hours, the colorless solution was evaporated to dryness, and acetic acid (100 ml) was added thereto.

Toluene sulfonic acid (1.0 g) was added and the solution was heated in a steam bath for 30 minutes. The solution was diluted with water and extracted with toluene. The extract was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was chromatographed on neutral alumina to obtain flavon-3-ene (6.3 g) as a buddy oil.

N. m. r. It was confirmed by spectrum. Multiplets at 5.8p.p.m. are characteristic of flav-3-ene.

Flav-3-ene was catalytically hydrogenated in acetic acid (60 ml) using 10% palladium carbon catalyst (150 mg) at room temperature and atmospheric pressure. 750 ml of hydrogen was absorbed for at least 3 hours. The reaction mixture was filtered, diluted with water and extracted with toluene and the evaporated extract was poured into chromatograph on neutral alumina eluting with toluene. The product was recrystallized from ethanol to give a flavan (2.75 g) melting point 43-44 ℃.

Example 89

Preparation of 4 ', 6-dichloroflavan

4, 5'-dichloro-2'-hydroxychalcone (7.32 g) was dissolved in methanol (100 ml) and sodium borohydride (1.89 g) was added in small portions. The reaction mixture was stirred at rt for 1 h, evaporated to dryness and diluted with water. The precipitated solid was filtered off, washed with water and then heated with acetic acid (100 ml) in a steam bath for 2 hours. Acetic acid was evaporated and the residue was dissolved in dichloromethane, and then washed with water, saturated sodium bicarbonate solution, and water, dried and evaporated. The residue was eluted with toluene to give chromatograph on alumina to give 4 ', 6-dichloroflavib-3-ene (3.84 g) as a colorless oil, which was n. m. γ. It was confirmed by spectroscopy.

Flavan (3.7 g) was dissolved in acetic acid (100 ml) and 10% palladium (100 mg) on a carbon catalyst was added and the solution was hydrogenated at room temperature and atmospheric pressure. After 1 hour 400 ml of hydrogen was absorbed. The solution was filtered, diluted with water and extracted with toluene. The extract was washed with water and saturated sodium bicarbonate solution, dried and evaporated. The residue was recrystallized to obtain 4 ', 6-dichloroflavan (2.70 g) and a melting point of 99-100 ° C.

Example 90-93

The compounds of Examples 90-93 were prepared from the specific compounds of Examples 44-47 by methods very similar to those of Example 80.

* 0.15mmHg = 20 ρa

Example 94

Preparation of Flavan

2-hydroxychalcone (28,5 g) was stirred with ethanol (500 ml) and sodium borohydride (9.45 g) was added in small portions at the same time. The solution which turned from red to pale yellow was left overnight at room temperature. Then the solvent was evaporated and the residue was exported to dichloromethane and washed with water. Evaporation of the solvent gave 2- (0-hydroxyphenyl) -1-phenylpropan-1-ol (24,4 g). 1.0 g of this carbinol was dissolved in concentrated sulfuric acid, and the solution was left at room temperature for 2 hours. The solution was poured into ice water and the viscous orange product was filtered off, washed with water, dried and poured onto chromatograph on alumina eluting with toluene. Eluent was evaporated to give flavan (0.20 g). This is petroleum ether, b.p. When recrystallized from 40-60 degreeC, the flavan and melting point 42-43 degreeC were obtained.

Example 95

Preparation of 4'-methoxyflavan

2-hydroxy-4'-methoxychalcone (12.7 g) was stirred with ethanol (200 ml) and sodium borohydride (3.8 g) was added in small portions. The solution was stirred at room temperature, the solution was evaporated and the residue washed with water and recrystallized from ethanol solution to give 3- (0-hydroxyphenyl) -1- (P-methoxyphenyl) propan-1-ol (8.60 g). ) And a melting point of 114-116 ° C. The total product was boiled for 2 hours with acetic acid (100 ml) under reflux.

The solution was evaporated and the residue was chromatographed on alumina, eluting with 4'-methoxyflavane (8.0 g) and a solvent 82-83 ° C., eluting with toluene.

Example 96

Preparation of 6-bromo-4-methoxyflavane

5-Bromo-2-hydroxy-4'-methoxychalcone (16.7 g) was suspended in ethanol (200 ml) and sodium borohydride (3.78 g) was added in small portions. The solution was stirred for 30 minutes and then left overnight. The solvent was evaporated and the residue was dissolved in chloroform and washed with water. Evaporation of the solvent gave the crude carbinol intermediate.

It was boiled with acetic acid for 2 hours under reflux. Upon cooling, 6-bromo-4'-methoxyflavane was produced by crystallization, and dried after filtration. Target object 10.2g, melting | fusing point 121-123 degreeC.

Example 97

Preparation of 2 ', 4'-dimethylflavane

2-hydroxy-2 ', 4'-dimethylchalcone (8.20 g) was suspended in ethanol (150 ml) and sodium borohydride (2.50 g) was added in small portions. The mixture was stirred for 30 minutes and the solution was left overnight. The solvent was distilled off and the residue was dissolved in chloroform and washed with water. Chloroform was evaporated to give crude intermediate carbinol. It was boiled for 2 hours with acetic acid (100 ml) under reflux. Evaporation gave an oily residue. This was added to the chromatograph on alumina eluting with toluene. The solvent was evaporated and the main fractions were distilled under vacuum to give 2 ', 4'-dimethylflavan, 4.80 g, b. p. 135-145 ° C / 0.8mmHg = 107Pa was obtained.

Example 98

Preparation of 4 ', 5, 7-trihydroxyflavane

4 ', 5, 7-trihydroxyflavanone (10.5 g) was stirred with acetic anhydride (50 ml) and sulfuric acid (5 drops) at room temperature for 2 hours and then poured into ice water. The product was extracted as ether and the extract was washed with water and then washed with sodium bicarbonate solution. The ether was evaporated to give 4 ', 5, 7-triacetoxyflavanone which was then dissolved in a mixture of tetrahydrofuran (250 ml) and ethanol (250 ml). Sodium borohydride (1.2 g) was added for at least 5 minutes and the solution was stirred for 30 minutes. Further borohydride (1.8 g) was added and stirring was continued for another 30 minutes.

The solution was carefully acidified by addition of glacial acetic acid (8 ml). The solvent was evaporated and the residual fraction was extracted with chloroform, washed with water, dried and evaporated.

The residue was boiled under reflux for 12 h with a mixture of ethanol (360 ml), water (240 ml) and imidazole (3.0 g). The solution was acidified with acetic acid (4.0 ml) and evaporated to dryness.

The residue was extracted with chloroform (2 x 250 ml) and the extract was evaporated and the residue was poured onto chromatograph on silica gel eluting with chloroform-methanol 95: 5. Thus, 0.9 g of 4 ', 5, and 7-trihydroxyflavane had a melting point of 212-215 ° C. (Recrystallized from acetic acid, 215-217 ° C.)

Example 99

Preparation of 4 '-(2-hydroxyethoxy) flavane

4'-hydroxyflavan (2.26 g), ethylene carbonate (8.8 g) and tetramethylammonium iodide (0.30 g) were heated together at 140 ° C. for 4 hours. Sodium hydroxide (6.5 g) and ethanol (250 ml) in water (20 ml) were added and the solution was boiled under reflux for 5 hours. The solution was filtered, diluted with water and extracted three times as ether.

The total ether extract was dried and then evaporated and the residue was poured onto chromatograph on neutral alumina. The product was eluted with chloroform and the solvent was evaporated and recrystallized from 60-80 ° C. petroleum ether to give 4 ′-(2-hydroxyethoxy) ciflavan (1.2 g) and a melting point of 84-85 ° C.

Example 100

Preparation of 6, 8-dichloroflavan

2,4-dichlorophenol (15.3 g), 10% sodium hydroxide solution (100 ml) and 40% formaldehyde solution (37.5 ml) were heated at 95--100 ° C. for 4 hours, then cooled and 2-N sulfuric acid (70 ml) Acidification was added. The precipitated oil was extracted with toluene and the extract was washed with sodium bicarbonate solution, dried and evaporated. The residue was recrystallized from boiling water to give 3, 5-dichloro-2-hydroxybenzyl alcohol (4.0 g) and a melting point of 81-82 ° C. (dried at 56 ° C./20 mmHg = 2660 Pa).

3, 5-dichloro-2-hydroxybenzyl alcohol (4.0 g) and styrene (2.19 g) were heated together at 190 ° C for 3 hours. The desired 6,8-dichloroflavan was obtained by adding the crude reaction mixture to chromatography on alumina eluting with toluene-petroleum ether (boiling point 60-80 ° C.) 1: 1. Then recrystallized from petroleum ether (boiling point 60-80 °) to obtain the target product of 2.60g, melting point 74-76 ℃.

Example 101

Preparation of 8-chloroflavan

3-chloro-2-hydroxybenzyl alcohol was prepared using Zinate et al. J. Prakt. Chem. 2 (152) (1939) prepared by the method of 126. This alcohol (3.96 g) was heated with styrene (2.6 g) at 180 ° C. for 2 hours. The reaction mixture was then poured onto chromatograph on alumina eluting with toluene. The eluate was evaporated to distillation under vacuum to yield 8-chloroflavan (0.12 g) boiling point 155-160 ° C./0.08 mmHg = 10.7 Pa.

Example 102

Preparation of Flavan

2-hydroxybenzyl alcohol (15 g) and styrene (75 g) were heated together at 230 ° C. under reflux for 1.5 h. Distillation gave flavan (13.9 g) from the precursor of styrene. When this was recrystallized from ethanol, the target object 10.3g and melting | fusing point 44-46 degreeC were obtained.

Example 103

Animal testing

Compound 4 ', 6-dichloroflavan was dissolved in olive oil B. P at concentrations of 3 mg / ml and 1 mg / ml. Subsequently, aliquots of these solutions were administered orally to mice.

After bolus administration, bleeding of the posterior orbit was performed every hour until half hour, 1 hour, and 7 hours after administration, and again 24 hours later. Plasma was collected from these bleedings and tested for antiviral action using the platelet blocking test described above. Minutes of each rat were collected after 24 hours and softened with a minimum amount of anhydrous alcohol. This liquid was tested for antiviral action by platelet inhibition test. Rat gallbladders were removed and each gallbladder was extracted as 10 μl of anhydrous alcohol. This extract was also tested by platelet arrest test. Antiviral activity was observed in plasma products up to 2 hours after administration of gallbladder and main extract. Plasma concentrations after 1 hour were assessed at 2-4 μM for the lower doses and 10 μM for the higher doses by viscosity on the standard curve. (The dose is about 30 mg / kg and 100 mg / kg body weight, respectively).

Example 104

Intranasal—Stomach of Disease in Vitro

Petri-plates were prepared and the church lobe of cells was covered with a layer of agarose gel as a platelet inhibition test. Compound, 4 ′, 6-dichloro flavan (1 μg) was dissolved in ethanol and applied to the lid of a Petri dish. When ethanol evaporated the compounds were allowed to diffuse into the interior of the lids and replaced on a Petri dish. Sufficient compound penetrated the agarose layer, causing the inhibition of overall platelet formation.

Example 105-166

The following compositions were prepared according to techniques known in the art of pharmacy.

Example 105

Inhalants to be used as inhalers were prepared from the following ingredients.

Example 106

Current suspensions to be used as non-dropping agents were prepared from the following ingredients.

Example 107

Pyratin capsules (size 0) were charged as 500 present compositions each containing 10 active ingredients per capsule.

Example 108

Gelatin capsules (size 1) were filled as 400 mg of the present composition containing 10 mg of active ingredient per every capsule.

Example 109

4 ', 6-dichloroflavan tablets

A tablet composition containing a mixture of 4 ', 6-dichloroflavan (10 mg), lactose (90 mg), corn starch (10 mg) and magnesium stearate (lmg) was prepared by wet granulation.

Example 110-165

Tablet compositions each containing one of the flavan derivatives of Examples 48-102 were prepared in a similar manner as in Example 109.

Example 166

Oil composition of 4 ', 6-dichloroflavan

1 'of 4', 6-dichloroflavan

Olive oil B.P 1g

The compound was dissolved in olive oil for use by oral administration.

Example 167

Various flavan derivatives were tested by the platelet reduction test described above and their ED ₅₀ 's against Vivirus serotype 1B were identified.

Claims (1)

Reducing the compound of formula (III), or reducing the compound of formula (IV) after cyclic reduction or cyclization, or condensing or producing the compound of formula (V) with the compound of formula (VI) Of a mono-, di- or tri-substituted structural formula (II) to convert the compound of formula (II) or to react with an inorganic, organic acid or base to form a salt of a compound of formula (II) having an amino or hydroxyl substituent. Method for preparing a flavan derivative or a pharmaceutically suitable salt thereof.

R ^A is two substituents selected from halogen, nitro, cyano, trifluoromethyl, (C ₁ -C ₄ ) alkylamino, (C | ₁ -C ₄ ) alkyl and hydrogen. R ^B is halogen, nitro, cyano, trifluoromethyl, (C ₁ -C _4), amino-alkyl, amino, (C ₁ -C4) alkyl, 4 '- except for the (C ₁ -C ₄₎ alkoxy ( C ₁ -C ₄₎ alkoxy, hydroxy, ethoxy, 4-hydroxy and the two substituents selected from hydroxy, except for hydrogen, provided that a substitution weight for R ^B are both hydrogen when R ^a is other than hydrogen or (C ₁ -C ₄ ) alkyl At least one of the substituents by R ^A and R ^B is a hydrogen atom. R ³ and R ⁶ are hydrogen atoms. R ⁴ and R ⁵ are the same or different hydrogen or halogen atoms or hydroxyl groups, where only one of R ⁴ and R ⁵ is a hydrogen atom, or R ⁴ and R ⁵ are double bonds or R ³ and R ⁴ One of those pairs R ⁵ and R ⁶ are oxo-, ketal, thioketal or dithioketal groups, one of the other pairs being a hydrogen atom, the other being hydrogen or a halogen atom or a hydroxyl group, or a tautomer or a salt thereof, and X is a hydroxyl group Or halogen atom.